Biological Material Fixed Region Enclosing Tip, Biological Material Fixed Region Treatment Apparatus, and Treatment Method Thereof

ABSTRACT

A biological material fixed region enclosing tip, a biological material fixed region treatment apparatus, and a treatment method thereof. An object is to enable processing to be performed while a fixing region is enclosed in an immovable state with respect to the tip form vessel, and to execute processing of high reliability with a simple apparatus. The biological material fixed region enclosing tip comprises: a tip form vessel having an installation opening part that is installable to a nozzle that performs suction and discharge of gas, and an opening through which inflow and outflow of fluid is possible by means of the suction and discharge of gas; a fixing region provided in the tip form vessel, in which a predetermined biological material is fixed or fixable in a plurality of different positions that are determined beforehand that are distinguishable from the exterior; and an enclosing section that encloses the fixing region within the tip form vessel such that the fixing region is able to make contact in an immovable state with the fluid that has flown into the tip form vessel from the opening.

CROSS REFERENCE

This application is a United States national phase application ofco-pending international patent application number PCT/JP2005/022776,filed Dec. 12, 2005, which claims priority to Japanese patentapplication number 2004-359202, filed Dec. 10, 2004, the disclosures ofwhich are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a biological material fixed regionenclosing tip, a biological material fixed region treatment apparatus,and a method thereof.

BACKGROUND ART

Conventionally, in a case where a series of reaction processes using aplurality of reagents and materials is performed on a target material,which becomes the subject of examination, for example, the targetmaterial is stored in a test tube by bonding to a microcarrier, such asa bead. Thereafter, a variety of reagents, or the like, are injectedinto the test tube, the carrier is separated by some method, the carrieris moved to another vessel, and other reagents, or the like, are furtherinjected, and processes such as heating are performed. For example, in acase where the carrier is a magnetic body, separation is performed bymeans of a magnetic field by attachment onto the inner wall of the testtube.

Furthermore, in regard to a process that performs examination of atarget material by using a plane form carrier, such as a slide, fixedwith, for example, a variety of oligonucleotides, the base sequencestructure of the target material is examined by performing a series ofreaction processes that, moves the carrier itself into a suspension inwhich the labeled target material is suspended, dispenses a variety ofreagents into the carrier itself, moves the carrier itself into acleaning solution, and moves the carrier to a measurement position of ameasuring device in order to perform measurement of the emitted light.

In order to perform these processes, the separation of the carrieritself, and the transport of the carrier itself is necessary, andconsequently, there is a problem in that there is concern in theprocesses being complex and time-consuming. Particularly, in regard to acase where these carriers themselves are transported, a large burden isplaced on the user in a case where it is performed manually, andfurthermore, there is also concern regarding cross-contamination.Moreover, a large scale device is necessary in a case where transport ofthe carrier itself is performed by means of a machine. Furthermore, in acase where separation of a non-magnetic carrier is performed, it isnecessary to separate by means of the size and specific gravity of thecarrier, and there is a problem in the process being complex andtime-consuming.

On the other hand, there is a method in which a test tube or a planeform carrier is not used, in which the reaction process is performedusing a pipette device comprising; a pipette tip provided with a liquidpassage, in which passage of a liquid is possible, a nozzle to which thepipette tip is installed, a magnetic device that exerts a magnetic fieldto the liquid passage of the pipette tip, and a suction and dischargemechanism that suctions and discharges liquid within the pipette tip.According to this method, as a result of suctioning a suspension inwhich a plurality of magnetic particles, in which various materials areretained on the surface, are suspended, and exerting a magnetic field atthe time of suctioning, the magnetic particles can be efficientlysuctioned into the liquid passage of the pipette tip, and separation, orthe like, can be performed.

In the case of using the apparatus, since the magnetic particles areable to pass through the liquid passage, in order to retain the magneticparticles within the pipette tip, attachment onto the inner wall byapplying a magnetic field is necessary. Consequently, in order toperform processing, there is a need to combine the suction and dischargecontrol, attachment control by means of a magnetic field, and movementcontrol of the pipette tip. Furthermore in regard to a case where thecarrier is a non-magnetic particle, there is a problem in thatseparation can not be performed by the device (Patent Documents 1 to 3).

[Patent Document 1] Japanese Patent Publication No. 3115501

[Patent Document 2] International Patent Publication No. WO96/29602

[Patent Document 3] International Patent Publication No. WO97/44671

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

Consequently, a first object of the present invention is in providing: abiological material fixed region enclosing tip, wherein by making itpossible to perform processing on a fixing region in which the variousmaterials are fixed or are fixable, while it is enclosed and retainedwithin a tip form vessel, attachment control and suction control forstoring and retaining the fixing region in the tip form vessel is madeunnecessary, complex reaction processes are simplified, and processingis made to be easily executed as a result of a small-scale deviceconfiguration; a biological material fixed region treatment apparatus;and the method thereof.

A second object is in providing: a biological material fixed regionenclosing tip, wherein by making it possible to perform the enclosingand the removal of a fixing region in which the various materials arefixed or are fixable, through a separate route to the route thatperforms suction and discharge of fluid or a material that is presentwithin the fluid, then a process in which the fixing region and thefluid is divided is made unnecessary, complex reaction processes aresimplified, and processing is made to be easily executed as a result ofa small-scale device configuration; a biological material fixed regiontreatment apparatus; and the method thereof.

A third object is in providing: a biological material fixed regionenclosing tip, wherein processing can be made efficient, and thereliability of processing and certainty of processing can be increasedby, in regard to a fixing region in which the various materials arefixed or are fixable, making it able to be easily enclosed by the tipform vessel that stores the same, and making processing with respect tothe fixing region easily executed; a biological material fixed regiontreatment apparatus; and the method thereof.

A fourth object is in providing: a biological material fixed regionenclosing tip, in which by suitably determining the shape and the sizeof the fixing region without being restricted to a magnetic bodymaterial, separation can be made easy, and therefore the breadth ofselections with respect to the material, increases, and the optimalmaterial for processing can be selected; a biological material fixedregion treatment apparatus; and the method thereof.

A fifth object is in providing: a biological material fixed regionenclosing tip, wherein automation in regard to consistent processing ismade easy; a biological material fixed region treatment apparatus; andthe method thereof.

Means for Solving the Problem

A first aspect of the invention is a biological material fixed regionenclosing tip comprising: a tip form vessel having an installationopening part that is installable to a nozzle that performs suction anddischarge of gas, and an opening through which inflow and outflow offluid is possible by means of the suction and discharge of gas; a fixingregion provided in the tip form vessel, in which a predeterminedbiological material is fixed or fixable in a plurality of differentpositions that are determined beforehand that are distinguishable fromthe exterior; and an enclosing section that encloses the fixing regionwithin the tip form vessel such that the fixing region is able to makecontact in an immovable state with the fluid that has flown into the tipform vessel from the opening.

Here, the “predetermined biological material” is a biopolymer, forexample, genetic material such as nucleic acids, proteins, sugars, sugarchains, or peptides, or chemical materials including low molecularweight compounds, and the biological material is used for detecting thebonding of a receptor biological material that possesses bondability tothe biological material as a ligand, capturing, separating, extraction,and the like. As the receptor, genetic material such as nucleic acids,proteins, sugar chains, peptides, or the like, that respectively possessbondability to genetic material such as nucleic acids, proteins, sugarchains, peptides, or the like, are appropriate. Furthermore, as thebiological material, or a replacement for the biological material, theorganism itself, such as cells, viruses, and plasmids, can be used.“Fixed”, for example, includes cases of physical adsorption orelectrical interaction in addition to the cases of covalent bonding andchemical adsorption. Furthermore, the predetermined chemical material isfixed to the fixing region; chemically, by physical adsorption, by aspecific reaction with a binding material provided fixed in anappropriate area, or by another method. Moreover, the reaction abilityor the bonding ability with the biological material may be increased byforming the fixing region with a porous material, a corrugated material,or a fibrous material. In order to perform fixing, a functional group isexpressed or generated in the fixing region. Consequently, byhydrolyzing the peptide bonds possessed by, for example, silk, or thelike, which comprises “polyamide type polymers”, totally aromaticpolyamides such as nylon (3-nylon, 6-nylon, 6,6-nylon, 6,10-nylon,7-nylon, 12-nylon, or the like) and PPTA (polyparaphenyleneterephthalamide), or heterocycle-containing aromatic polymers, thefunctional groups used for fixing the biological material is expressedor generated. Examples of functional groups that are bondable with thebiological material include carboxyl groups —COOH, amino groups —NH₂,and the derivatives thereof. Here, the pore diameter suitable for fixingthe biological material is, for example, several micrometers or less.

The “fixing region” is a region where one type of more of the biologicalmaterials are fixed or are fixable, and is enclosed in the tip formvessel by the enclosing section. Examples of the fixing region includefor example regions which are formed on the internal surface of thevessel, and on plane form carriers of plate-shaped carriers and the likehaving various sizes. “Fixing region” is preferably a plurality ofdifferent positions that are determined beforehand that aredistinguishable from the exterior. These may be planar regions that canbe specified by a two dimensional position coordinate, and are not onlya flat surface but may also be a curved surface.

In the case where one or more types of biological materials is fixed tothe fixing region, the predetermined types of biological materials canbe arranged so as to become a predetermined relationship to thepredetermined positions of the fixing region. In that case, as a resultof a solution containing a biological material that is labeled by alabeling material comprising a luminescent material, such as afluorescent material in which there is the possibility of bonding withthese biological materials, making contact with the fixing region, thepresence of bonding with these biological materials is measured bymeasuring the luminescence at each position, and as a result of this,the structure, the characteristics, and the presence of the targetbiological material can be analyzed. Furthermore, by fixing one or moretypes of biological materials to the fixing region, the targetbiological material can be separated and extracted. “Contact in animmovable state” means that the whole fixing region is able to makecontact with the fluid without being moved relative to the tip formvessel by the fluid flowing inside the tip form vessel.

Examples of the “enclosing section” include, for example in the casewhere the fixing region is provided on the internal surface of thevessel: a lid member provided on the tip form vessel, for covering theopening part from the outside of the tip form vessel for enclosing thefixing region inside the tip form vessel, by covering the distributionopening part for distribution of the biological material to the fixingregion; an attachment member for attaching the plane form carrierserving as the fixing region, to the tip form vessel; or a protrusionmember with the plane form carrier attached as a fixing region thatforms the tip form member.

The “tip form vessel” is a vessel provided with an installation openingpart and an opening. The installation opening part is provided on theupper end, the opening is provided on the lower end, and it ispreferable for the opening to be narrower than the installation openingpart, and to be provided on the end of the narrow tube, which isinsertable into various vessels. In this case it is preferable toprovide a fixing region forming section that forms the fixing region,between the narrow tube and the installation opening part, tocommunicate between these. In regard to the fixing region formingsection, it is preferable for it to have a wide tube that is formedwider than the narrow tube. In regard to the wide tube and the narrowtube, this is not limited to a case having a typical tube shape such aswith a wide diameter tube and a narrow diameter tube. For example,instead of a wide diameter tube, this may be a vessel that has a thinrectangular box shape, having the installation opening to the nozzle onan upper end portion, and having a shape to communicate the thindiameter portion with the lower end. In regard to the material of thetip form vessel, it is preferable for the portion that encloses thefixing region to be translucent in order to enable optical measurementsto be performed. If the fixing region is provided in a portion otherthan the narrow tube, inside the tip form vessel, then the fixing regioncan be widened. Examples of the material of the tip form vessel includeresins such as polyethylene, polypropylene, polystyrene, and acrylic,glass, metals, and metal compounds. In regard to the size, for example,it is a size in which several microliters to several hundred microlitersof liquid is storable in the tip form vessel.

A second aspect of the invention is a biological material fixed regionenclosing tip wherein the fixing region is provided on the plane formcarrier which is detachably attached inside the tip form member, and thetip form member has a carrier insertion opening insertable by the planeform carrier, and the enclosing section is attached inside the tip formmember, so that fluid that has flown in from the opening inside the tipform member is able to contact with the plane form carrier.

Here the “carrier”, with respect to the tip form vessel, is a solid bodyhaving a size capable of insertion or removal from the carrier insertionopening. Normally this cannot pass through the opening. Inside the tipform vessel, the minimum amount of liquid that is handled is a volume offor example several microliters to several hundred microliters, and itis necessary for the whole surface of the carrier to be able to contactwith the liquid. Therefore, it is appropriate if the volume of the spacesurrounded by the surface of the carrier inserted into the fixing regionforming section, and the internal surface of the vessel, has a volumecorresponding to the minimum amount. The carrier itself may betranslucent, or may be non translucent. In the case where this is nontranslucent, both surfaces can be used as the fixing region.Furthermore, the carrier is preferably stored in the fixing regionforming section provided between the installation opening part and thenarrow tube.

Consequently, the size of the opening of the tip form vessel forsimplifying the suction and the discharge of the liquid quantity, andthe size of the carrier for enabling it to pass through the carrierinsertion opening part is considered. Here the “plate-shaped carrier”may be a carrier where a plurality of different positions that aredetermined beforehand that are distinguishable from the exterior, can bespecified by a two dimensional position coordinate. It may be a carrierhaving not only a flat surface but also one having at least one curvedsurface. Even if this is a plate-shaped carrier, a thin film formcarrier, or a block form carrier, it is sufficient if a plane surface ora curved surface is formed that can be specified by at least one twodimensional position coordinate.

The carrier is a solid body that is, for example, fixed such that it isarranged with a spacing, or is fixable, such that one or more types ofthe predetermined types of biological materials become a predeterminedrelationship to the predetermined positions. In that case, as a resultof a solution containing a biological material that is labeled by alabeling material comprising a luminescent material, such as afluorescent material in which there is the possibility of bonding withthese biological materials, making contact with the carrier, thepresence of bonding with these biological materials is measured bymeasuring the luminescence at each position, and as a result of this,the structure, the characteristics, and the presence of the targetbiological material can be analyzed.

Since the plane form carrier is insertable to inside the tip form vesselfrom the carrier insertion opening, fixing of the biological materialcan be performed on the outside of the tip form vessel. Consequently,the fixing process for the biological material is easy. The carrierinsertion opening may be used in conjunction with the installationopening part, or may also be provided separate to the installationopening part. In the case where this is provided separate to theinstallation opening part, then as the enclosing section, a lid memberfor closing the carrier insertion opening is necessary.

As the tip form vessel, there is one having translucence such that lightemitted by the plane form carrier can be measured. Furthermore, forexample, preferably this has a portion formed in an approximatequadratic prism shape that matches with the size and shape of the planeform carrier.

The carrier is, for example, a porous body or a solid body in which afunctional group that is able to bond to the biological material isgenerated or expressed at the surface, or a combination of both. Forexample, it is formed by a fibrous material such as rubber, silicone,cellulose or nylon, a resin, glass, or a metal.

Since “in the enclosing section fluid that has flown in from the openinginside the tip form member is able to contact with the plane formcarrier”, it is necessary to attach by providing the enclosing sectionon the tip form vessel inside, and so that the face fixed with thebiological material is not a tight fit with the inner wall of the tipform member. The enclosing portion may be: one where the tip form vesselis provided modified or processed; one where the tip form vessel isprovided separately; or one where a separately provided the tip formvessel and one where processing has been performed on the walls and thelike of the tip form vessel, are assembled together. As one where thetip form vessel is used as is, there is one where a protrusion portionis provided that protrudes towards the center of the tip form vessel. Asthe one where the tip form vessel is provided separately, there is forexample a lid member that closes the opening provided on the tip formvessel in order to enclose the fixing region. The screws, adhesive, weldmetal for attaching the carrier or the lid member to the tip formmember, are also included with the lid member.

The “lid member” is preferably a member of a plane form of for example athin film or a thin plate. By forming an electrically conductive thinfilm as described later, then this may also be heated and cooled.

A third aspect of the invention is a biological material fixed regionenclosing tip wherein the tip form vessel has a distribution openingthat is capable of distributing the biological material with respect tothe fixing region, and the enclosing section has a lid member thatcovers the distribution opening, so that fluid that has flown in fromthe opening can contact with the fixing region.

A fourth aspect of the invention is a biological material fixed regionenclosing tip wherein the fixing region is provided on an internalsurface of the tip form vessel, and the distribution opening is providedon a wall facing the internal surface.

Here for the tip form vessel, for example this has a portion formed inan approximate quadratic prism shape, and the fixing region is providedso as to occupy a predetermined internal surface of one side face of thequadratic prism of the tip form vessel, and the distribution opening hasa wall face along the predetermined internal surface, which is providedso that the fixing region can be reached by a tip of a dispensing unitor the like from the outside that has passed through the other sideface.

A fifth aspect of the invention is a biological material fixed regionenclosing tip wherein the volume of a space in which liquid is storablewithin the tip form vessel with the fixing region enclosed is severalmicroliters to several hundred microliters.

By setting the volume of the tip form vessel in this manner, then evenif liquid of a small amount, for example liquid of a volume of severalmicroliters to several hundred microliters, is drawn in to the tip formvessel, the liquid can uniformly or evenly contact with the surface ofthe carrier. This small amount, in conventional biological analysis, inparticular DNA analysis, is an amount of material that is easilyextracted from an organism and handled. Furthermore, as the tip formvessel, a large tube that communicates with the carrier storing sectionmay be provided in addition to the carrier storing section that storesthe carrier. For example by making this several times to several tentimes the volume of the carrier storing section, then various liquidamounts can be handled.

A sixth aspect of the invention is a biological material fixed regionenclosing tip wherein the fixing region is formed on one face of theplane form carrier, and on the tip form vessel there is provided a fluidcontact opening part for enabling contact between the fixing region ofthe plane form carrier and fluid that has been introduced from theopening, and the enclosing section has an attaching member that attachesthe plane form carrier from outside of the tip form carrier so that thefixing region of the plane form carrier is positioned in the contactopening part.

Here the attaching member is a member for attaching the plane formcarrier to the tip form vessel, and for example is an attachment devicesuch as adhesive, screws, or an engaging member. The plane form carrieror the plane form member of the thin film carrier or the like, may besuch as to form an electroconductive member having a predeterminedelectrical resistance value as described later.

A seventh aspect of the invention is a biological material fixed regionenclosing tip wherein the entire wall of the tip form vessel, or aportion thereof, is formed by an electroconductive member that has apredetermined electrical resistance value.

Here, by providing the electroconductive member to the tip form vessel,heat generation can be induced by making a terminal that is connected toan electrical circuit provided on the exterior come into contact withthe electroconductive member, and by flowing an electrical currentthrough the electroconductive member, which has a predeterminedresistance value. The resistance value is controlled by a controlsection mentioned below, based on the processing contents.

Moreover, as the “predetermined electrical resistance value”, it is avalue in which the heat generation that is necessary for theelectroconductive member to achieve a temperature according to theobject can be performed by flowing a fixed electrical current within theelectroconductive member. For example, in terms of the surfaceresistance value, it is, for example, several hundred ohms to severalohms per unit area, and furthermore, the resistance value at whichinduction heating is made possible is, for example, several ohm cm ormore. As the conductive thin film, for example, there is a case where itcomprises a single type of material that has a predetermined electricalresistance, or there is a case where two or more types of materials thathave different resistance values are joined, adhered, deposited, fused,welded, bonded, attached, or pasted. In the former case, the temperaturedepends on the magnitude of the electrical current value, which is theelectromagnetic signal, and in the latter case, as a result of thePeltier effect, the temperature depends not only on the electricalcurrent value but also the orientation of the current, and not onlyheating, but cooling also becomes possible.

Examples of the “electroconductive member” include metals, metalliccompounds such as metal oxides, conductive materials such as alloys,semiconductors, metalloids, and conductive resins, a combination ofthese conductive materials with non-conductive materials such asceramics, glass, and synthetic resins, or it may be a combinationbetween conductive materials. For example, there are cases of aluminum,aluminum oxide, tin oxide, iron, an iron alloy, a nichrome alloy, and amember formed by two types of different conductive materials that havebeen bonded by means of bonding, welding, or joining. By flowing anelectrical current to these members, or in the case of iron or an ironalloy, by applying a temporally oscillating magnetic field, thesemembers can be inductively heated. In a case where two types ofconductive materials have been joined, heating and cooling can beperformed by means of the orientation of the electrical current.

Examples of the shape of the electroconductive member include a linearform, a thin-film form, a foil form, a film form, a thin plate form, aplate form, a long and narrow shape, and a layer form. Theelectroconductive member may be bonded, welded or deposited on anon-conductive member in order to reinforce the electroconductivemember. The electroconductive member is controlled to a predeterminedtemperature by means of the “electromagnetic signal” (an electricalsignal or a magnetic signal). Thermodynamic signals resulting from theapplication of heat or cold air are excluded from the electromagneticsignal.

In regard to the wall, the inner wall face thereof faces into the tipform vessel, the outer wall face thereof is on the exterior of the tipform vessel, and it is a tip form vessel wherein the interval betweenthe inner and outer wall faces is integrally formed. That is to say, theportion of the wall that is sandwiched by the inner wall face and theouter wall face of the tip form vessel is, for example, a metal, aresin, or the like, or it is formed as a wall in a solid state in whichthese have been bonded such that they are not freely divided.Consequently, as the electroconductive member that has been formed asthe entire wall or a portion of the wall, in a case where this has anelectroconductive member that is freely separable from the wall, thenfor example, electroconductive members that simply only make contactwith the wall, electroconductive members that are freely detachablyinstalled to the wall by means of a screw, or the like,electroconductive members that are freely detachably provided withrespect to a separate member that is installed to the wall by welding,or the like, and electroconductive members that are completely separatedfrom the wall, are able to be divided, and are therefore excluded.Consequently, if the electroconductive member is provided such that thewall of the tip form vessel becomes approximately the thickness demandedas the wall of the tip form vessel, then the size of the tip form vesseland the scale of the entire device is controlled, and it can be handledwithout an awareness of the presence of the heating device.

An eighth aspect of the invention is a biological material fixed regiontreatment apparatus comprising: a nozzle head that has one or aplurality of consecutive nozzles that perform suction and discharge ofgas; a suction and discharge mechanism that performs suction anddischarge of gas via the nozzles; one or two or more biological materialfixed region enclosing tips that are installed or are installable to thenozzles, in which a fixing region, to which biological material isfixable or is fixed, is enclosed; a stage to which a liquid storagesection group, in which a variety of liquids are stored or are storable,is provided; a movement device that relatively moves the nozzle headwith respect to the liquid storage section group; and a control sectionthat controls the suction and discharge operations comprising theamount, the speed, the frequency, the time, or the position of thesuction and discharge of the nozzles based on; the structure of thebiological material fixed region enclosing tip, the material conditionscomprising the type of biological material that is fixed to the fixingregion or is present within the fluid, the concentration, the amount ofliquid, and the coordinate position containing the storage position ofthe liquid, and the processing contents.

Here the “biological material fixed region enclosing tip” comprises, forexample; a tip form vessel that has an installation opening part that isinstalled to the nozzle, and an opening through which inflow and outflowof fluid is possible by means of the suction and discharge of the gas, afixing region in which a predetermined biological material is fixed oris fixable at a plurality of different positions determined beforehandthat are identifiable from the exterior, that is provided in the tipform vessel, and an enclosing section that encloses the fixing regionwithin the tip form vessel such that the fixing region is able to makecontact in an immovable state with the fluid that has flown into the tipform vessel from the opening.

Moreover, since there are “one or two or more biological material fixedregion enclosing tips that are installed or are installable to thenozzles”, the biological material fixed region enclosing tips arearranged in the middle of the vessel group, and the nozzles can beinserted into the installation opening part and automatically installedand used. Furthermore, by providing a mechanism for removing thebiological material fixed region enclosing tips from the nozzles inwhich they are installed, then consistent processing includingprocessing from installation of the biological material fixed regionenclosing tips to their removal removing can be performed.

Here, the “processing contents” are, for example, reaction, cleaning,transporting, dispensing, separating, extracting, heating, cooling,clarifying, measuring, mixing, deviating, elution, stirring, or thelike, or a series of these processes that are combined according to apredetermined order or a predetermined time schedule according to aprocessing objective while including overlaps. “Time” includes theduration time or the timing of suction and discharge. By setting theduration time or the timing, intermittent, continuous or periodicsetting of the suction and discharge is made possible.

In the case of “reaction” processing, for example, according to thematerial conditions, in regard to the vessel position in which thecorresponding reagent is stored, a control in which; the suction anddischarge that is determined by the conditions is performed at apredetermined speed, and suction and discharge is repeated at a liquidquantity of, for example, 80 percent of the capacity of the carrierenclosing region of the tip form vessel, is performed. In regard to thefrequency of the suction and discharge thereof, the determined controlis performed according to the material conditions. In the case of“cleaning” processing, for example, according to the materialconditions, in regard to the vessel position in which the cleaningsolution is stored, a control in which; the suction and discharge thatis determined according to the process is performed at a predeterminedspeed, and suction and discharge is repeated a predetermined number oftimes, is performed. In the same manner, control of the suction anddischarge according to the process is performed. In regard to the“speed”, for example, since in a case where the handled material is DNA,the size thereof is small compared to proteins, it is necessary toincrease the speed in order to increase the encounterability betweenDNA. Furthermore, the speed differs depending on the contents ofprocessing, and in the case of cleaning and stirring, the speed of thesuction and discharge thereof is low compared to a case where thereaction process is performed.

The “structure of the biological material fixed region enclosing tip”also includes the shape of the tip, the position of the enclosed fixedregion, the shape and the characteristics of the carrier, the shape ofthe enclosing section, or the like. Determining the action of thesuction and discharge according to the “type of the biological material”means that, for example, in a case where it is generally smaller thanthe size of proteins, such as in the manner of genetic material such asDNA, it is easier to handle if the handled liquid quantity is small, andthe speed is fast. This is because the smaller the size, theencounterability generally becomes low.

A ninth aspect of the invention is a biological material fixed regiontreatment apparatus further comprising a light reception device thatreceives light from the fixing region stored within the tip form vessel.

In regard to the light reception by means of the light reception device,there is a case where it is collectively performed with respect to aplurality of biological material fixed region enclosing tips that areinstalled to a nozzle head that has a plurality of consecutive nozzles,and there is a case where light reception is serially performed for eachof the biological material fixed region enclosing tips by means of thelight reception device. In the latter case, it is performed by using amovement device that relatively moves between the light reception deviceand the vessel while relatively transporting the tip or the lightreception device serially one at a time. In that case, since themeasurement is performed by shifting the time, some kinds of reagents,for example, the PCR reaction solution in the previous process of PCR,in a case where extraction of DNA is performed, or a substrate solutionto be injected in the case of chemiluminescence, need be dispensedimmediately before reaction or a fixed time before reaction.Consequently, dispensing is not performed simultaneously, and it ispreferable for dispensing to be performed by temporally shifting one ata time and providing a time difference. In a case where fluorescence ismeasured, a luminescent device that irradiates a predeterminedexcitation light into the vessel is further provided.

A tenth aspect of the invention is a biological material fixed regiontreatment apparatus wherein a space in which liquid is storable withinthe tip form vessel, is several microliters to several hundredmicroliters.

Consequently, in regard to the liquid storage section provided on theexterior of the biological material fixed region enclosing tip, theseveral microliters to several hundred microliters of liquid must bestorable such that it is able to be suctioned into the tip through theopening.

An eleventh aspect of the invention is a biological material fixedregion treatment apparatus wherein a temperature raising and loweringbody that raises and lowers the temperature as a result of a signal fromthe exterior is provided in the vicinity of, making contact with, orable to be in the vicinity of or making contact with, the outside of thetip form vessel of the biological material fixed region enclosing tip.

Here, the “temperature raising and lowering body” refers to a member ora device that is able to raise or lower the temperature thereofaccording to a signal from the exterior. The “signal” is, in a casewhere the temperature raising and lowering body is an electroconductivemember, an electromagnetic signal, that is to say, a signal resultingfrom electricity or magnetism. It is also possible to detect thetemperature resulting from the temperature raising and lowering body andgenerate the signal based on the temperature.

It is preferable for the temperature raising and lowering body to berelatively movably provided with respect to the biological materialfixed region enclosing tip. Furthermore, in this case, the controlsection, in addition to control of the suction and discharge,consequently controls the temperature control based on the processingcontents.

A twelfth aspect of the invention is a biological material fixed regiontreatment apparatus wherein the nozzle head has a collective nozzle headin which a plurality of consecutive nozzles are arranged along thecolumn direction and an individual nozzle head that has at least onenozzle, the suction and discharge mechanism has a collective suction anddischarge mechanism that simultaneously performs suction and dischargeof gas with respect to the plurality of consecutive nozzles of thecollective nozzle head, and an individual suction and dischargemechanism that individually performs suction and discharge of gas withrespect to each nozzle of the individual nozzle head, and the movementdevice has, a nozzle head movement device that relatively moves thecollective nozzle head and the individual nozzle head in the rowdirection with respect to the liquid storage section group, and atransporting route that includes a column transporting route that is onthe movement route of the collective nozzle head and along the columndirection and a row transporting route that is on the movement route ofthe individual nozzle head and along the row direction, and has a queuedroute transporting device that transports a transport storage section,in which tips that have been detached from the collective nozzle head orliquid that has been discharged from the collective nozzle head arerespectively storable, along the transporting route.

Here, there is no need for the “column direction” and “row direction” tonecessarily be orthogonal such as in an X direction (horizontaldirection) and a Y direction (vertical direction), and a case where theyare oblique is acceptable. The collective nozzle head and the individualnozzle head may be individually movable. Furthermore, if the queuedroute transporting device has a row transporting route and a columntransporting route on the movement route of the nozzle head, forexample, it may be a case where it has a closed transporting route, suchas a square shape or a polygonal shape, or it may be a case where it hasan open transporting route. The “transport storage section” is a portionthat stores the tip or the liquid in the transporting device, and it ispreferable if, at the very lest, it has the same number of transportstorage sections as the number of nozzles of the collective nozzle head.

A thirteenth aspect of the invention is a biological material fixedregion treatment apparatus wherein the nozzle head has a plurality ofconsecutive collective nozzles and one individual nozzle arranged alongthe column direction, the suction and discharge mechanism simultaneouslyperforms suction and discharge of gas with respect to the collectivenozzles and the individual nozzle of the nozzle head, and the movementdevice has, a nozzle head movement device that relatively moves thenozzle head along the row direction with respect to a stage that has theliquid storage section group, and a transporting route that includes acolumn transporting route that is on the movement route of thecollective nozzles and along the column direction and a row transportingroute that is on the movement route of the individual nozzle and alongthe row direction, and has a queued route transporting device thattransports a transport storage section, in which tip form vessels thathave been detached from the collective nozzle or liquid that has beendischarged from the collective nozzle head are respectively storable,along the transporting route.

A fourteenth aspect of the invention is a biological material fixedregion treatment apparatus wherein a light reception device, whichreceives light from the transport storage section, is provided at apredetermined position along the transporting route of the queued routetransporting device.

A fifteenth aspect of the invention is a biological material fixedregion treatment method comprising: a fixing step for fixing apredetermined biological material to a fixing region such that it isassociated with a predetermined position by a predeterminedrelationship; an enclosing step for forming a biological material fixedregion enclosing tip by enclosing within a tip form vessel which has aninstallation opening part that is installable to one or a plurality ofconsecutive nozzles that perform suction and discharge of gas, and anopening, through which inflow and outflow of fluid is possible by meansof the suction and discharge of gas, the fixing region fixed with thebiological material such that the fixing region is able to make contactin an immovable state with the fluid that has flown into the tip formvessel from the opening; and a reaction step for moving a nozzle towhich one or two or more of the biological material fixed regionenclosing tips has been installed to a-predetermined liquid storagesection, and bringing into contact and reacting the biological materialfixed to the fixing region and a solution stored in the liquid storagesection by controlling the operation of suction and discharge, whichcomprises the amount of suction and discharge via the nozzle, the speed,the frequency, the time, and the location, based on the structure of thebiological material fixed region enclosing tip, the material conditionscomprising the type of biological material that is fixed to the fixingregion or is present in the solution, the concentration, the amount ofsolution, or the position coordinate which includes the storage positionof the solution, and the processing contents.

A sixteenth aspect of the invention is a biological material fixedregion treatment method that, following the reaction step, has a lightreception step for receiving light from the fixing region of thebiological material fixed region enclosing tip.

A seventeenth aspect of the invention is a biological material fixedregion treatment method wherein the reaction step has a temperatureraising and lowering step for raising and lowering the temperaturewithin the biological material fixed region enclosing tip.

An eighteenth aspect of the invention is a biological material fixedregion treatment method wherein the fixing step is performed bydistributing in a fixing region provided on an internal surface of thetip form vessel, the biological material that has passed through adistribution opening provided in the tip form vessel, and the enclosingstep is performed by covering the distribution opening with a lidmember, which is attached from outside of the tip form vessel.

EFFECTS OF THE INVENTION

According to the first aspect of the invention, the fixing region whichis fixed or is fixable with various types of biological materials,enables processing to be performed while the fixing region is enclosedin an immovable state with respect to the tip form vessel. Consequentlysince the fixing region is immovable with respect to the tip formvessel, the various positions on the fixing region can be specifiedaccurately and reliably. Definitely/positively/accurately.

Furthermore, according to the present aspect of the invention, in regardto the fixing region in which a variety of types of biological materialsare fixed or are fixable, the enclosing and the removal thereof isperformed by a separate route to the route in which suction anddischarge of fluid, or the material that is suspended in the fluid, isperformed. Consequently, a process for separating the fluid and thefixing region, for example the carrier attachment control and the like,is made unnecessary, the complex reaction process is simplified, andprocessing can be easily executed by a small-scale device configuration.

According to the present aspect of the invention, by merely performingsuction and discharge of fluid while enclosing the fixing region withinthe tip form vessel, and by moving the tip form vessel, a variety ofprocesses, for example, reaction, washing, temperature control,separation, stirring, dispensing, clarifying, isolation, elution, andextraction can be performed, and therefore, processing can be performedefficiently, quickly, and easily.

Furthermore, according to the present aspect of the invention, since thereaction with the biological material fixed to the fixing region upuntil measurement can be performed while enclosed within the tip formvessel, the target process can be performed consistently, without beingmanually handled, and automatically, and therefore, a process that has ahigh reliability can be performed with certainty. Moreover, according tothe present aspect of the invention, by finely setting the aspect of thesuction and discharge, for example the speed, the volume, and the time,based on the process contents and the shape of the tip and the like,then reliability can be increased, and it can be made to handle avariety of processes. Therefore it has generality and diversity.

According to the second aspect of the invention, in addition to theeffects described for the first aspect, the fixing region is provided onthe face form carrier that is detachably attached inside the tip formvessel and is formed in a size where it can be inserted from the carrierinsertion opening. Therefore, regarding the fixing process for thebiological material, after performing this outside the tip form vessel,it can be enclosed and hence processing is simplified. Furthermore, byusing the carrier insertion opening in common with the installationopening part, forming of the tip form vessel is simplified. Moreover,time and effort for manufacture can be reduced. Furthermore, since thearea of the opening portion is small, liquid spill and the like can bereliably prevented making handling easy.

By providing the carrier insertion opening part separate to theinstallation opening part, a large carrier which is not restricted bythe size of the nozzle can be inserted. Hence various types ofprocessing are possible giving wide used.

Furthermore, since the plate-shaped carrier is attached so as to enablecontact with the liquid, this can be made to reliably contact with theliquid that has been introduced to inside the tip form vessel.

Moreover, since the carrier is attached so that it is immovable withrespect to the tip form vessel, there is no influence on the position ofthe carrier due to the introduction of liquid, and hence in processesaccompanying the suction and discharge of liquid, reliable measurementscan be performed.

According to the third aspect of the invention, in addition to theabovementioned effects, the distribution opening part capable of passingthe biological material and distributing with respect to the fixingregion, is provided on the tip form vessel, and the biological materialis distributed through the distribution opening part.

Consequently, it is not necessary to take out the fixing region tooutside of the tip form vessel in order to perform the fixing process ofthe biological material, and there is no direct contact with a personshand. Hence processing with a high reliability can be performed.

Moreover, since it is not necessary to determine the nozzle installationopening part in consideration of the size of the carrier, there is noneed to use special order items for the nozzle, and hence manufacturingcost can be kept down.

According to the fourth aspect of the invention and the eighteenthaspect of the invention, by providing the fixing region on the internalsurface of the tip form vessel, it is not necessary to use a separatelymanufactured carrier. Hence the number of parts can be reduced, andmanufacturing costs can be reduced. Furthermore, since the internal wallis made the fixing region, the flow of fluid is not disturbed, andsmooth suction and discharge can be performed.

According to the fifth aspect of the invention, within the tip formvessel, the volume of the space which is possible between the surface ofthe fixing region enclosed in the tip form vessel and the internalsurface of the tip form vessel, is kept to the volume of the liquid usedfor processing (a minimum amount). As a result contact between theliquid drawn in to inside the tip form vessel, and the whole surface ofthe carrier is possible, so that with respect to a minimum amount ofliquid, handling of a high reliability is possible.

According to the sixth aspect of the invention, since the fixing regionis made so that it is formed on one surface of the plate-shaped carrieror the thin film form carrier provided separate to the tip form vessel,the biological material can be easily fixed. Furthermore, by coveringthe opening formed in the tip form vessel by means of the carrier, thefixing region can be reliably enclosed inside the tip form vessel.

According to the seventh aspect of the invention, an electroconductivemember having a predetermined electrical resistance value is formed onthe entire, or on a part of, the wall of the tip form vessel. By flowingan electrical current to the electroconductive member that is formed onthe entire, or on a part of, the wall of the tip form vessel, andperforming heat generation of the electroconductive member, and henceheating or cooling the fixing region and the liquid stored in the tipform vessel, temperature control of the reaction can be performed.

Consequently, compared to a case where a heating device, such as aheater, is provided on the outside of the wall of the tip form vessel,since it is directly making contact with the inside of the tip formvessel, the reflection of heat by the wall is prevented, the heat can bemore efficiently transmitted with respect to the inside of the tip formvessel, the thermal efficiency is high, and an accurate temperaturecontrol can be performed.

Furthermore, since the wall of the tip form vessel is formed by anelectroconductive member, the thermal efficiency is high, it is notnecessary to provide a heating device that is larger than necessary,such as a metallic block, to the outside of the tip form vessel, and itis sufficient to only provide the driving device to the exterior.Consequently, the structure of the exterior is simplified, and theentire device scale can be reduce.

Since an optical temperature raising and lowering body can be providedto the tip form vessels beforehand, it is not necessary to provide aheating device that satisfies a variety of conditions, to the exterior,and it has generality and diversity.

Since the electroconductive member directly makes contact with theinside of the tip form vessel, temperature control of the liquid can beperformed with a high accuracy and faithfulness.

The time from applying the signal to the tip form vessel and theelectroconductive member for heating or cooling with respect to theliquid until the liquid temperature becomes a uniform temperaturedistribution is shortened, and the process can be quickly andefficiently performed.

Furthermore, since in particular the temperature and the time ofhybridization can be controlled in parallel or in series to the suctionand discharge or the movement processing, then processing up untilcleaning of the array, detection, and measurement can be controlledconsistently.

According to the eighth aspect of the invention, the biological materialfixed region enclosing tip, in which a fixing region, to which abiological material is fixed or is fixable, is enclosed within the tipform vessel, is installed to the nozzle, and the amount, the speed, thefrequency, or the position of the suction and discharge with respect tothe nozzle is controlled based on the material conditions, whichcomprise the shape of the tip thereof, the shape of the fixing region,the type of the biological material that is fixed on the fixing regionor is to be suspended, the amount of liquid, and the coordinate positionwhich includes the storage position of the liquid, and the processingconditions, which comprise the time and the temperature of incubation,or the processing contents.

Consequently, according to the present aspect of the invention, as wellas using a biological material fixed region enclosing tip with apredetermined structure, by performing fine controls with respect to thesuction and discharge, processes such as reaction, stirring andcleaning, on the biological material which is fixed or is fixable to thefixing region that is enclosed within the tip, can be easily,consistently, quickly, and efficiently performed with a highreliability. Furthermore, according to the present aspect of theinvention, by changing the contents of the control, a variety ofprocesses can be handled, and therefore, it has generality anddiversity.

According to the ninth aspect of the invention or the sixteenth aspectof the invention, by receiving light from the fixing region, processingup until measurement can be performed more consistently, quickly, andefficiently with a high reliability.

According to the tenth aspect of the invention, within the tip formvessel, by suppressing the capacity of the space capable of storing theliquid in a state where the fixing region is enclosed in the tip formvessel, the contact between the liquid suctioned into the tip formvessel and the entire surface of the fixing region is made possible, andhandling with a high reliability with respect to the microamount ofliquid is made possible.

According to the eleventh aspect of the invention or the seventeenthaspect of the invention, temperature control is performed on thebiological material fixed region enclosing tip, and consequently on thefixing region enclosed therein, by approaching a temperature raising andlowering body from the exterior. Consequently, compared to a case wheretemperature control is performed and reaction with the fixing region isperformed by heating a vessel provided outside the tip, the reaction canbe more efficiently performed with certainty. Moreover, sincetemperature control can be performed on the biological material fixedregion enclosing tip, as it is, this can be performed with a simplecontrol, and is thus suitable for automation.

According to the twelfth aspect of the invention, the collective nozzlehead and the individual nozzle head is simultaneously movable in the rowdirection, and a queued route transporting device having a transportroute provided with the row transporting route and the columntransporting route, is provided on the movement route of the collectivenozzle head and the individual nozzle head. Consequently, as a result ofthe transporting device, it is processable by either the collectivenozzle head or the individual nozzle head, a plurality of nozzles and asuction and discharge mechanism are not arranged in a queue form, and avariety of complex processes are made possible by a simple and compactstructure using a small number of nozzles.

Furthermore, at the time the suction and discharge process is performedwith respect to a plurality of processing subjects, in regard to thecommon processing items, by collectively performing processing using thecollective nozzle head, and in regard to the processing items in whichit is necessary to individually perform processing, by performingprocessing individually using the individual nozzle head, a variety ofprocesses can be efficiently and quickly performed.

In particular, in regard to a case where a measurement is performedindividually, it is suitable for a case where a necessary reagent isadded directly before the measurement thereof, or a case where a reagentwith a need for maintaining a predetermined temperature is addeddirectly before processing that is performed individually.

According to the thirteenth aspect of the invention, as well asdemonstrating the same effects as the aforementioned twelfth aspect ofthe invention, since suction and discharge of the collective nozzle andthe individual nozzle can be simultaneously performed with the samesuction and discharge mechanism, the structure is simpler.

According to the fourteenth aspect of the invention, by providing alight reception device at, at the very least, one position on thetransporting route of the queued route transporting device, processesthat handle the nozzles that are processed with a plurality ofconsecutive nozzles, and serial measurement using a small number oflight reception devices, can be performed. Consequently, the device canbe simplified. In particular, since reagents that only become necessarydirectly before light reception by the light reception device, can beserially charged by the individual nozzle head directly before lightreception, light reception can be performed efficiently with a highreliability.

According to the fifteenth aspect of the invention, the biologicalmaterial fixed region enclosing tip, in which a fixing region, to whicha biological material is fixed or is fixable, is enclosed within the tipform vessel, is installed to the nozzle, and the amount, the speed, thefrequency, or the position of the suction and discharge with respect tothe nozzle is controlled based on the material conditions, whichcomprise the structure of the tip thereof, the type of the biologicalmaterial that is fixed on the fixing region or is to be suspended, theamount of liquid, and the coordinate position which includes the storageposition of the liquid, and the processing conditions, which comprisethe time and the temperature of incubation, or the processing contents.Consequently, according to the present aspect of the invention, as wellas using a biological material fixed region enclosing tip with apredetermined structure, by performing fine controls with respect to thesuction and discharge, processes such as reaction with the suctionedliquid, the stirring thereof, and cleaning, on the biological materialwhich is fixed or is fixable to the fixing region that is enclosedwithin the tip, can be easily, consistently, quickly, and efficientlyperformed with a high reliability. Furthermore, by changing the contentsof the control, a variety of processes can be handled, and therefore, ithas generality and diversity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing showing a biological material fixed region enclosingtip according to a first embodiment.

FIG. 2 is a cross-sectional view showing a biological material fixedregion enclosing tip according to a second embodiment.

FIG. 3 is an exploded perspective view showing a biological materialfixed region enclosing tip according to another aspect of the secondembodiment.

FIG. 4 is an exploded perspective view showing a biological materialfixed region enclosing tip according to a fourth embodiment.

FIG. 5 is a perspective view of a biological material fixed regionenclosing tip according to the fourth embodiment.

FIG. 6 is an exploded perspective view showing a biological materialfixed region enclosing tip according to a fifth embodiment.

FIG. 7 is a plan view showing an entire biological material fixed regiontreatment apparatus according to a sixth embodiment.

FIG. 8 is a side view showing a biological material fixed regionenclosing tip treatment apparatus according to a sixth embodiment.

FIG. 9 is a flow diagram showing a biological material fixed regiontreatment method according to a seventh embodiment.

FIG. 10 is a flow diagram showing a biological material fixed regiontreatment method according to an eighth embodiment.

FIG. 11 is a flow diagram showing a biological material fixed regiontreatment method according to a ninth embodiment.

FIG. 12 is a plan view showing an entire biological material fixedregion treatment apparatus containing another biological material fixedregion enclosing tip treatment apparatus according to the sixthembodiment.

BEST MODE FOR CARRYING OUT THE INVENTION

According to the present invention, as well providing an enclosingsection to the tip form vessel, and enclosing a biological materialfixed region in which the biological material is fixed or is fixable toa predetermined position, such that it becomes able to make contact withthe fluid, by making the fixed positions measurable from the exterior, aconsistent automation of a process from a reaction between thebiological material and the biological material contained in the liquidthat has flowed in until arriving at the measurement, is achieved.

Next, the embodiments of the present invention are explained based onthe drawings. The explanation of the embodiments should in no way beinterpreted as limiting the present invention unless particularlyspecified.

FIG. 1( a) to FIG. 1( d) show a biological material fixed regionenclosing tip 11 according to a first embodiment of the presentinvention. FIG. 1( a) shows a front view of the biological materialfixed region enclosing tip 11, which is one having a tip form vessel 12which is translucent, that has a thin approximate prism shape fixingregion forming section 13, and a narrow tube 15 that is formed narrowerthan the fixing region forming section 13 and a nozzle to which it isinstalled (not shown in the figure). An upper end 13 a of the fixingregion forming section 13 is formed in a cylinder shape, and on theupper edge thereof is provided a cylinder shape installation openingpart 14 that is to be installed to a nozzle which is not shown in thedrawing, that performs suction and discharge of gas. An opening 16,through which fluid inflow and outflow is possible by means of thesuction and discharge of gas, is provided on the end of the narrow tube15. The fixing region forming section 13 has a size such that aplate-shaped carrier 18 provided with a fixing region 17 can be passedthrough the installation opening part 14 of the upper end 13 a andinserted. The installation opening part 14 also corresponds to thecarrier insertion opening. On the plate-shaped carrier 18, various typesof biological materials determined beforehand are fixed or are fixableto previously determined positions 17 a.

An annular attachment member 18 a serving as the enclosing section, isengaged with the inside of the upper end 13 a and thus attached to thetip form vessel 12. The plate-shaped carrier 18 is immovably attachedwith respect to the annular attachment member 18 a and hence withrespect to tip form vessel 12, as is evident from the side view of FIG.1( b) and the cross-section of FIG. 1( c).

A filter 19 capable of passing a gas, is installed on the somewhat lowerside of the installation opening part 14 on the inside of the upper end13 a of the fixing region forming section 13, and on the upper side ofthe annular attachment member 18 a.

As shown by the perspective drawing of FIG. 1( d), the annularattachment member 18 a is provided with an annular rim 20, and opposedsquare shape cut outs 21 on the bottom side of the annular rim 20 oneither side of the central axis. The annular attachment member 18 a isattached so that an upper edge of the plate-shaped carrier 18 is grippedin the portion of the cut outs 21. The aforementioned fixing region isformed on the plate-shaped carrier 18.

To continue, FIG. 2( a) to FIG. 2( d), show a biological material fixedregion enclosing tip 22 according to a second embodiment of the presentinvention. FIG. 2( a) shows a front view of the biological materialfixed region enclosing tip 22. The biological material fixed regionenclosing tip 22 has a tip form vessel 23 which is translucent, and hasa thin approximate prism shape fixing region forming section 24, and anarrow tube 26 that is formed narrower than the fixing region formingsection 24 and a nozzle to which it is installed (not shown in thefigure). An upper end 24 a of the fixing region forming section 24 isformed in a cylinder shape, and on the upper edge thereof is provided acylinder shape installation opening part 25 that is to be installed to anozzle which is not shown in the drawing, that performs suction anddischarge of gas. An opening 27, through which fluid inflow and outflowis possible by means of the suction and discharge of gas, is provided onthe end of the narrow tube 26.

On the largest side face of the side faces of the fixing region formingsection 24, which has the greatest area, is formed a fixing region 28 towhich a predetermined biological material is fixed or is fixable at apreviously determined position. Furthermore, the largest side facefacing the aforementioned largest side face of the fixing region formingsection 24 has a distribution opening section 29 capable of distributingthe predetermined biological material with respect to the fixing region28. Moreover, regarding the distribution opening section 29, in order toenclose the fixing region 28 inside the tip form vessel 23, this is madeto be closable by a plate-shaped lid member 30 serving as an enclosingsection. Furthermore, on the upper portion 24 a of the fixing regionforming section 24 is provided a filter 31 through which gas can pass.FIG. 2( b) and FIG. 2( d) show a state where the lid member 30 isremoved from the tip form vessel 23. Regarding the size of thedistribution opening section 29, this must have a shape or size suchthat a predetermined biological material can be distributed by adispensing tip or the like, in the fixing region 28. For example, thedistribution opening section 29 is formed so that this becomes equal tothe area and the shape of the fixing region 28. In the figure referencesymbol 28 a indicates a fixing position or a fixable position for thepredetermined biological material.

FIG. 3 shows an exploded perspective view of a biological material fixedregion enclosing tip 32 according to another aspect of the secondembodiment of the present invention. The biological material fixedregion enclosing tip 32 has a tip form vessel 33 which is translucent,and has a thin approximate prism shape fixing region forming section 34,and a narrow tube 36 that is formed narrower than the fixing regionforming section 34 and a nozzle to which it is installed (not shown inthe figure). An upper side of the fixing region forming section 34 has acylinder shape installation opening part 35 that is to be installed tothe nozzle which is not shown in the drawing, that performs suction anddischarge of gas. An opening 37, through which fluid inflow and outflowis possible by means of the suction and discharge of gas, is provided onthe end of the narrow tube 36. On the largest side face 34 a of the sidefaces of the fixing region forming section 34, which has the greatestarea, is formed a fixing region 38 to which a predetermined biologicalmaterial is fixed or is fixable at a previously determined position.

Furthermore, the largest side face facing the aforementioned largestside face 34 a of the fixing region forming section 34 has adistribution opening section 39 capable of distributing thepredetermined biological material with respect to the fixing region 38.Moreover, regarding the distribution opening section 39, in order toenclose the fixing region 38 inside the tip form vessel 33, this is madeto be closable by a plate-shaped lid member 40 serving as an enclosingsection, that is attached to the outer wall of the tip form vessel 33.Regarding the size of the distribution opening section 39, this musthave a shape or size such that a predetermined biological material canbe distributed by a dispensing tip or the like, in the fixing region 38.For example, the distribution opening section 39 is formed so that thisbecomes equal to the area and the shape of the fixing region 38. In thefigure reference symbol 38 a indicates a fixing position or a fixableposition for the predetermined biological material.

FIG. 4 is an exploded perspective view and perspective view showing abiological material fixed region enclosing tip 41 according to a thirdembodiment.

The biological material fixed region enclosing tip 41 has a tip formvessel 42 which is translucent, and has a thin approximate prism shapefixing region forming section 43, and a narrow tube 45 that is formednarrower than the fixing region forming section 43 and a nozzle to whichit is installed (not shown in the figure). An upper side of the fixingregion forming section 43 has a cylinder shape installation opening part44 that is to be installed to the nozzle which is not shown in thedrawing, that performs suction and discharge of gas. An opening 46,through which fluid inflow and outflow is possible by means of thesuction and discharge of gas, is provided on the end of the narrow tube45. The fixing region forming section 43 has a size capable of storingthe plate-shaped carrier 49 with the fixing regions 48 provided on oneflat face thereof. The plate-shaped carrier 49 is attached to the innerwall of largest side face 43 a of the side faces of the fixing regionforming section 43, which has the greatest area, so as to be immovableby means of attaching members 49 a such as screws which are provided infour corners of the plate-shaped carrier 49. Furthermore, on the sideface facing the largest side face 43 a there is provided a carrierinsertion opening 47 for storing the plate-shaped carrier 49 from theoutside.

The plate-shaped carrier 49 is for example formed by a slide glass. Thesize of the slide glass is for example 6.2 mm×30 mm, and the surface isprocessed in order to fix various oligonucleotides serving as DNAprobes. At this time, when enclosed in the fixing region forming section43, the space formed in the fixing region forming section 43 forms aspace with around 0.5 mm or less between the walls, and having a volumeapproximately coinciding with the minimum volume for handling, so thatexperiments with good efficiency are possible.

Furthermore, to cover the carrier insertion opening 47, a thin plate lidmember 50 for enclosing the plate-shaped carrier 49 is provided. The lidmember 50 corresponds to the enclosing member. On a portioncorresponding to the largest side face of the fixing region formingsection 43 of the approximate rectangular shape there is provided anengaging portion 43 b which engages the lid member 50.

The biological material fixed region enclosing tip 41 in a state withthe plate-shaped carrier 49 having the fixing regions 48 stored, and thefixing regions 48 enclosed is shown in FIG. 5.

FIG. 6 is an exploded perspective view showing a biological materialfixed region enclosing tip 51 according to a third embodiment. Thebiological material fixed region enclosing tip 51 has a tip form vessel52 which is translucent, and has a thin approximate prism shape fixingregion forming section 53, and a narrow tube 55 that is formed narrowerthan the fixing region forming section 53 and a nozzle to which it isinstalled (not shown in the figure). An upper side of the fixing regionforming section 53 has a cylinder shape installation opening part 54that is to be installed to the nozzle which is not shown in the drawing,that performs suction and discharge of gas. An opening 56, through whichfluid inflow and outflow is possible by means of the suction anddischarge of gas, is provided on the end of the narrow tube 55.

A fixing region 58 to which a predetermined biological material is fixedor is fixable at a previously determined position, is formed on oneplane face of a plate-shaped carrier 57 serving as a plane form carrier.The rear face of the plane face is to be covered with an electricallyconductive thin film 57 a, and by flowing an electrical current to theelectrically conductive thin film 57 a, this can be heated. Furthermore,of the side faces of the tip form vessel 52, on the largest side facehaving the largest area, there is provided a fluid contact opening part59 for enabling contact between the fixing region 58 of the plane formcarrier 57 and the fluid that has been introduced from the opening 56.So that the fixing region 58 of the plane form carrier 57 forms an innerwall of the tip form vessel 52, the plane form carrier 57 is attached byan adhesive or screws or the like to the outer wall of the tip formvessel 52 so as to close off the fluid contact opening part 59.Consequently, the plane form carrier 57 corresponds to the enclosingsection.

FIG. 7 is a planar schematic view representing an entire biologicalmaterial fixed region treatment apparatus 10 according to a fourthembodiment of the present invention.

The biological material fixed carrier treatment apparatus 10 has: abiological material fixed region enclosing tip processing device 80,which has a suction and discharge mechanism, and installs the biologicalmaterial fixed region enclosing tip 35 on a nozzle, and performs asuction and discharge process with respect to the biological materialfixed region enclosing tip 32; a tip processing region 81 forperforming, suction and discharge with respect to the biologicalmaterial fixing region, dispensing into an exterior vessel, stirring,washing, extraction, transport, reaction, or the like, by performingsuction or discharge of a suspension containing various specimens,reagents, or the like, within the biological material fixed regionenclosing tip 35; a reagent dispensing region 82 for dispensing areagent for measurement, to within the biological material fixed regionenclosing tip by using a single nozzle possessed by the biologicalmaterial fixed region enclosing tip processing device 80; and ameasurement region 83 that obtains optical information for executingmeasurement in regard to the biological material fixed region that isenclosed within the biological material fixed region enclosing tip 32.

In regard to the biological material fixed region enclosing tipprocessing device 80 shown in FIG. 7 and FIG. 8, suction and dischargeof gas is performed using a nozzle that is communicated with acollective suction and discharge mechanism and an individual suction anddischarge mechanism. The biological material fixed region enclosing tipprocessing device 80 has a collective nozzle head 84 that has aplurality (eight consecutive in this example) of nozzles 117 that arearranged in the column direction (the vertical direction in thedrawing), and an individual nozzle head 84′ that has a single nozzlethat performs suction and discharge independently to the collectivenozzle head 84. In regard to the collective nozzle head 84, as opposedto the suction and discharge being simultaneously performed by thecollective suction and discharge mechanism with respect to the pluralityof consecutive nozzles 117, the suction and discharge is performed withrespect to the nozzle (one in this example) of the individual nozzlehead 84′ independently to the eight consecutive nozzles 117 by anindividual suction and discharge mechanism. In the drawing, thereference symbols of the components, or the like, that belong to theindividual nozzle head 84′ are indicated by attaching a dash to thereference symbol of the components, or the like, that belong to thecorresponding collective nozzle head 84.

In FIG. 8, only the collective suction and discharge mechanism of thecollective nozzle head 84 is shown. This collective suction anddischarge mechanism has an engaging section 116 that is provided to asomewhat upper section than the lower end of the nozzle 117, and a rod112 for sliding a plunger 115 a within a cylinder 115 that is joined tothe nozzle 117. Furthermore, the eight rods 112 are installed in eightrespective notch sections that are provided on the edge of a drivingplate 123 (reference symbol 123′ represents a driving plate of theindividual suction and discharge mechanism) in which vertical movementis independently possible for each, such that they sit on eightconsecutive end sections 112 a (reference symbol 112 a′ represents anend portion of the individual suction and discharge mechanism), thathave a larger diameter than the diameter of the rods 112 and protrude inthe radial direction. Hence, the collective nozzle head 84 and theindividual nozzle head 84′ simultaneously move in the row direction (thehorizontal direction or the left and right directions on the drawing).

Furthermore, as shown in FIG. 8, the driving plate 123 is joined to anut section 113 that screws to a ball screw 114. The rods 112 areenergized in the downward direction at all times by means of a springthat is provided to the cylinder 115. Consequently, the rods 112 areable to be raised by the nut sections 113 in a case where they move inthe upward direction, but in a case where they are lowered in thedownward direction, they are lowered not as a result of the nut sections113, but because of the spring force. The ball screws 114 arerotationally driven by a motor 110 (reference symbol 110′ represents themotor of the individual suction and discharge mechanism) provided to across-sectional U-shaped supporting member 111 (reference symbol 111′represents the supporting member of the individual suction and dischargemechanism), and as a result, the driving plate 123 and the eight rods112 vertically move.

In regard to the raising and lowering of the nozzle itself, although itis independent of the individual nozzle head 84′ and the collectivenozzle head 84, the horizontal movement in the row direction (the leftand right directions in FIG. 7) is integrated. The individual nozzlehead 84′ is, in regard to the reagent dispensing region 82, used fordispensing reagents for measurement within the biological material fixedregion enclosing tip 32, that are stored within the tip storage section102. In the reagent dispensing region 82, a reagent storage section 77that stores predetermined reagents that are suctioned by the nozzle head84′, and a predetermined tip 78, which is in a state where it isinstallable to the nozzle head 84′, for example, a filter-containingtip, are provided. Furthermore, the reagent storage section 77 is, forexample, provided with a constant temperature device for retaining thereagents at a constant temperature.

In FIG. 8, the inside of the chassis 87, has a ball screw 119, a nutsection 120 that screws to the ball screw 119, and a supporting body 121that has the supporting member 111, to which the nut section 120 isinstalled, at one end. Furthermore, on the chassis 87, a motor 88 thatrotationally drives the ball screw 119 is provided. By means of avertical movement mechanism resulting from these components, the nozzle117 is vertically movable.

A temperature raising and lowering device 71 is provided on the lowerside of the chassis 87. In regard to the temperature raising andlowering device 71, it is formed along the column direction such that ithas a height and a width that primarily makes it approachable to, orable to make contact with, the fixing region forming section which isprincipally the eight tips that are installed to the eight consecutivenozzles, it has a heating plate 73 that has a heater in the interior,and nine heating walls 72, which are installed to the heating plate 73,that have a heater in the interior and are provided protruding such thatthey respectively sandwich the tips from both sides, and this heatingplate 72 and these nine heating walls 72 are, as a whole, formed in acomb form. Furthermore, it is preferable for the heating plate 73 to beformed such that it has a shape that is matched to the shape of the tipthat becomes the subject of temperature control. Here, the heating plate73 and the heating walls 72 correspond to the temperature raising andlowering body.

The temperature raising and lowering body 71 approaches, or makescontact with, the tip installed to the nozzle 117 of the collectivenozzle head 84, and it has a motor 74 for making it possible to heat thetip, a ball screw 76 a that is rotationally driven by the motor 74, anut section 75 that screws onto the ball screw 76 a, and a movement rod76 b that joins the nut section 75 and is movable in the left and rightdirections in the drawing, and also joins to the heating walls 72 andthe heating plate 73.

The bottom side of the temperature raising and lowering device 71 has amotor 89 for making it possible to remove the tip that has beeninstalled to the nozzle 117 of the collective nozzle head 84, a ballscrew 91 a that is rotationally driven by the motor 89, a nut section 90that screws onto the ball screw 91 a, and a movement rod 91 b that joinsthe nut section 90 and is movable in the left and right directions inthe drawing, and which moves a claw 122 in the left and right directionsin the drawing.

The biological material fixed region enclosing tip processing device 80is provided such that it is suspended from the upper side, and it ismovably provided by means of an X axis (row direction) movementmechanism not shown in the drawing, which utilizes a direct actingmechanism, such that it covers all regions of the biological materialfixed region treatment apparatus 10 and the other necessary regions.

Furthermore, returning to FIG. 7, the tip processing region 81 has: acartridge vessel 92, which has eight consecutive specimen wells 92 athat store the suspension in which the specimen is suspended; a matrixform vessel 95, which, as well as storing various tip type columns 96and 97, has a 5 column×8 row well having a liquid storage section column99 that stores the product material; and eight cartridge vessels 100that have a prepackable well 100 a for storing various reagents ormaterials that are necessary for executing processing, or storing theresulting material of processing. Amongst the cartridge vessels 101,reference symbol 100 b represents an incubator well that is providedwith a heat block.

Furthermore, barcodes 92 b are attached to the specimen storage wells 92a, that display information relating to the respective specimensthereof. The barcodes 92 b are read by a barcode reading section 93,which reads the barcode 92 b, by moving such that it scans. Referencesymbol 93 a is a movement mechanism that drives the barcode readingsection 93.

A movable conveyor 103, which is made to surround the surroundings ofthe eight consecutive cartridge vessels 100, is provided along a squareshaped transporting route that has the column transporting routes 103 aand 103 c on the movement route of the collective nozzle head 84 of thebiological material fixed region enclosing tip processing device 80along the column direction (the vertical direction or the Y direction inthe drawing), which is parallel to the arrangement direction of theeight consecutive nozzles, and a row transporting route 103 b on themovement route of the individual nozzle head 84′ along the row direction(the horizontal direction or the X direction), which is perpendicular tothe arrangement direction.

The conveyor 103 corresponds to the queued route transporting device,and a total of 32 tip storage sections 102, which correspond to thetransport storage section, are movably joined together with the conveyor103, such that they correspond to the spacing between the nozzles.Consequently, in regard to a position such as the one shown in FIG. 7,suction and discharge of liquid with respect to the two columns of tipstorage sections 102 arranged on the column transporting routes 103 aand 103 c are possible by means of the eight consecutive nozzles of thebiological material fixed region enclosing tip processing device 80.Furthermore, by means of the series of nozzles of the individual nozzlehead 84′, which is provided such that suction and discharge is possibleindependently to the group of eight consecutive nozzles of thecollective nozzle head 84 of the biological material fixed regionenclosing tip processing device 80, within the transporting route, whichhas been arranged in a square shape as the queued route transportingdevice, the row transporting route 103 b of the lower side, that is tosay, with respect to the selected tip storage sections 102 within thereagent dispensing region 82, reagents that correspond to an object, forexample, a substrate liquid, or the like, in chemiluminescence, can bedispensed. In particular, it is dispensed directly before reaction ofthe PCR reaction liquid, or the like, in PCR preprocessing for a casewhere DNA extraction is performed. Here, the tip storage sections 102are parts that store or retain the biological material fixed regionenclosing tips with the nozzles 117 detached, so that measurement ispossible from outside.

Furthermore, within the measurement region 83, a measurement position104 is provided within the square shaped transporting route of thequeued route transporting device, and in regard to the measurementposition 104, excitation light is irradiated within the biologicalmaterial fixed region enclosing tip by means of the trigger light source105, and measurement is performed by receiving the generated light atthe light receiving section 106. Consequently, processing can beperformed according to the processing object for each tip.

Next, based on FIG. 9, as DNA processing according to the presentembodiment, SNPs (single nucleotide polymorphism) typing is explainedfor a case where the biological material fixed region enclosing tip 32is used.

At the plurality of SNP positions that are to be measured, anoligonucleotide, which has a possibility of hybridization, that has abase sequence, is fixed to the fixing region 38 as a probe material. Inorder to perform fixing to the fixing region 38, a functional group isgenerated or expressed beforehand at the surface of the fixing region38, it is bonded with the probe material, and the surface is cleanedwith a suitable solvent.

For example, at SNP1 (a first position), there is a possibility of twotypes, the base T or the base C, and at SNP2 (a second position), thereis a possibility of two types, the base G or the base A.

A fixing position 38 a of the fixing region 38 fixed with a basesequence for determining the base T at SNP1, a fixing position 38 b ofthe fixing region 38 fixed with a base sequence for determining the baseC at SNP1, a fixing position 38 c of the fixing region 38 fixed with abase sequence for determining the base G at SNP2, and a fixing position38 d of the fixing region 38 fixed with a base sequence for determiningthe base A at SNP2 are, as shown in FIG. 9( a), formed on the major sideface 34 a with the greatest area of the side faces of the fixing regionforming section 34 of the tip form vessel 33 which has a translucency.At this time a dispensing mechanism that passes the fluid through thedispensing opening part 39 of the tip form vessel 33 is used to dispensethe fluid. On completion of dispensing, the dispensing opening part 39is covered by the lid member 40 of the enclosing section and therebysealed. As a result, the biological material fixed region enclosing tip32 is formed.

For example, in regard to eight test subjects, a case where the SNPstyping position of a respective plurality of positions (two positions inthis example) are attempted to be simultaneously determined, isexplained. In this case, in a step S1, in regard to a biologicalmaterial fixed region enclosing tip 32 that is formed in this manner,the nozzle 117 of the biological material fixed region enclosing tipprocessing device 80 is installed to the installation opening part 35provided on the upper side of the fixing region forming section 37thereof.

On the other hand, specimens such as the following are stored in theeight specimen storage wells 92 a provided in the tip processing region81. That is to say, the genome is respectively extracted from the bloodof the eight test subjects, and amongst these genomes, the fragmentsthat contain a plurality of positions of the SNPs typing positions areamplified by a thermal cycler, a material that is labeled by afluorescent material is generated, and this is stored per test subjectin the eight specimen wells 92 a. Furthermore, in the eight consecutivecartridge vessels 100, a BW buffer solution is stored in the wells 100 ato 100 c thereof.

In a step S2, as shown in FIG. 9( a), the collective nozzle head 84 ofthe biological material fixed region enclosing tip processing device 80is advanced in the row direction by means of the movement device, thenarrow tubes 36 are simultaneously inserted into the specimen storagewells 92 a, and the insides of the fixing region forming sections 34 aresimultaneously filled by performing suction of a suspension that isinside the specimen storage wells 92 a.

In a step S3, as shown in FIG. 9( b), the fixing region 38 inside thetip form vessel 33 and the suspension are brought into sufficientcontact via the nozzle, for example, by stirring as a result ofrepeating suction and discharge ten times at a predetermined speed s1(for example, approximately 200 microliters/sec), and in an amount v1(for example, approximately 400 microliters).

Then, in a step S4, as shown in FIG. 9( c), the DNA fragments within thesuspension, which have been labeled by a fluorescent material, bond tothe oligonucleotide at the fixing position of the fixing region 38amongst the positions of the SNP by means of hybridization. The residualliquid is discharged into the specimen storage well 92 a.

In a step S5, as shown in FIG. 9( d), in regard to the biologicalmaterial fixed region enclosing tip processing device 80, the biologicalmaterial fixed region enclosing tip 32 that encloses the fixing region38, for which the reaction has been completed, is transported to thelocation of the wells 100 a of the eight consecutive cartridge vessels100, and with respect to the BW buffer solution, cleaning is performedby repeating suction and discharge ten times, for example, by means of apredetermined speed s2 (for example, from approximately 760 to 1700microliters/sec) in a microamount v2 (for example, approximately 500microliters). Furthermore, as shown in FIG. 9( e), the same operation isrepeated with respect to the wells 100 b and 100 c.

In a step S6, in regard to the biological material fixed regionenclosing tip 32, for which cleaning has been completed, the collectivenozzle head 84 is moved to the position of the tip storage section 102that is stopped on the column transporting route 103 a of the conveyor103, separated from the plurality of consecutive nozzles 117 provided tothe collective nozzle head 84 a by means of the claw 122 and stored inthe tip storing section 102, and transported along the transportingroute by driving the conveyor 103. At the time the tip storage section102 reaches the row transporting route 103 b, following suction of apredetermined reagent by moving the individual nozzle head 84′ to thereagent storage section 77, amongst the eight tip storage sections 102that are stopped along the row transporting route 103 b, dispensing of areagent for measurement is performed from the installation opening part35 of the selected biological material fixed region enclosing tip 32,for example, as the predetermined reagent. Thereafter, it is transportedto the measurement position 104 provided on the transporting route bydriving the conveyor 103. As shown in FIG. 9( f), an excitation light isirradiated at the measurement position 104, and the light within thefixing region forming section 34 is received at the light receivingsection 106. By performing measurement of the light emission position,analysis of the structure of the target material is performed.

Next, based on FIG. 10, the processing procedure with respect to anallergy test as a protein analysis example is described for a case wherethe biological material fixed region enclosing tip 41 is used.

Various allergen materials, for example, materials obtained from cedarpollen, ragweed, mites, mold, or the like, are fixed to the plate-shapedcarriers 49 provided with the fixing regions 48. In order to fix theallergen materials to the fixing positions 48 a and 48 b of theplate-shaped carriers 49, a functional group is generated or expressedbeforehand on the surface of the plate-shaped carriers 49. Theplate-shaped carrier 49 fixed with these allergen materials, is insertedinside the fixing region forming section 43 which has a translucency bypassing through the installation opening part 47. Then after insertion,the lid member 50 is engaged with the engaging section 43 b of thefixing region forming section 43, is installed by welding as a result ofadhesion, ultrasonic waves or heat, and is enclosed, and the biologicalmaterial fixed region enclosing tip 41 is formed.

As shown in FIG. 10, in a step S11, in regard to the biological materialfixed region enclosing tip 41 obtained in this manner, the nozzle 117 ofthe biological material fixed region enclosing tip processing device 80is installed to the installation opening part 44 provided to the upperside of the fixing region forming section 43 thereof.

On the other hand, blood collected from the eight test subjects isstored in the specimen storage wells 92 a provided to the tip processingregion 81, and in the eight consecutive cartridge vessels 100, a 50 mMTBS buffer solution and a pH 8, 1% BSA solution are stored in the wells100 a, a cleaning solution comprising a 50 mM TBS buffer solution and apH 8, 0.005% Tween solution are stored in the wells 100 b to 100 f, anda liquid that suspends an anti-human IgE antibody that has been labeledwith a fluorescent material is stored in the wells 100 g.

In a step S12, as shown in FIGS. 10( a) and (b), the solutions arestirred by performing suction and discharge of an amount v3 (a volume ofthe carrier inside the tip filled by liquid; for example, approximately500 microliters) of the solution stored in the wells 100 a at a speed s3(slow so as not to form bubbles; for example, approximately 760microliters/sec), and the fixing region 48 of the surface of theplate-shaped carrier 49 is blocked (shutoff).

In a step S13, as shown in FIG. 10( c), cleaning is performed with the50 mM TBS buffer solution and pH 8, 0.005% Tween solution that is storedin the wells 100 b. Furthermore, in a step S14, as shown in FIG. 10( d),the biological material fixed region enclosing tip 41 installed to thenozzle is moved to the specimen storage well 92 a, the blood stored inthe specimen storage well 92 a is suctioned into the tip form vessel 42and brought into contact, and the IgE antibody in the blood and theallergen material is reacted within the tip form vessel 42 for 30minutes at 37 degrees. At that time, in order to maintain the tip formvessel 42 interior at a constant temperature, it is heated such that thetip form vessel 42 is sandwiched from both sides and nine heating walls72 and heating plates 73 of the temperature raising and lowering device71, which are arranged in a comb form, approach both sides of the eightconsecutive biological material fixed region enclosing tip 41.Consequently, the inside of the tip form vessel 42 interior can beefficiently heated with certainty.

Next, in a step S15, as shown in FIG. 10( e), the biological materialfixed region enclosing tip 41 is moved to the wells 100 c of thecartridge vessel 100. The aforementioned cleaning solution is stored inthe wells 100 c, and cleaning is performed by repeating suction anddischarge ten times at, for example a speed s4 (for example, fromapproximately 760 microliters to 1700 microliters/sec) and in an amountv4 (for example, approximately 500 microliters). Furthermore, thebiological material fixed region enclosing tip 41 is transported to thewells 100 d, and cleaning is repeated.

Next, in a step S16, as shown in FIG. 10( f), the collective nozzle head84 is moved to the wells 100 g, the suspension is suctioned and broughtinto contact with the plate-shaped carrier 49 in order to react with theanti-human IgE antibody stored in the wells 100 g, which has beenlabeled with fluorescent light, and it is maintained at 37° C. for 30minutes. Also in this case, as mentioned above, the inside of the tipform vessel 43 is heated by approaching the heating wall 72 and theheating plates 72 of the temperature raising and lowering device 71 suchthat they sandwich both sides of the biological material fixed regionenclosing tip 41.

In a step S17, as shown in FIG. 10( g), it is moved to the wells 100 eof the cartridge vessel 100, and the fixing region 48 is cleaned byperforming suction and discharge of the stored cleaning solutionapproximately ten times, for example, at a speed s5 (for example, fromapproximately 760 microliters to 1700 microliters/sec), and in an amountv5 (for example, 500 microliters). The same operation is repeatedfollowing movement to the wells 100 f.

Next, in a step S18, in regard to the biological material fixed regionenclosing tip 41, the collective nozzle head 84 is moved to the tipstorage section 102 that is stopped on the column transporting route 103a of the conveyor 103, separated from the plurality of consecutivenozzles 117 provided to the collective nozzle head 84 by means of theclaw 122 and stored in the tip storing section 102 that is arranged onthe column transporting route 103 a, and transported along thetransporting route by driving the conveyor 103. At the time the tipstorage section 102 reaches the position of the row transporting route103 b, the individual nozzle head 84′ is moved to the reagent storagesection 77, the predetermined reagent is suctioned, and then amongst theeight tip storage sections 102 that are stopped along the rowtransporting route 103 b, it is moved to the selected biologicalmaterial fixed region enclosing tip 41, and dispensing of thepredetermined reagent is performed from the installation opening part 44of the selected biological material fixed region enclosing tip 41.Thereafter, at the measurement position 104 provided on the transportingroute, as shown in FIG. 10( h), light from the plate-shaped carrier 49is received and measured at the light receiving section 106, thefluorescence strength of the particle surface is measured, and thereacted allergen material is specified.

Next, based on FIG. 11, a protein analysis example using a biologicalmaterial fixed region enclosing tip 51 with the protein fixed to thefixing region 58, is explained. In the process, in FIG. 11( a), severaltypes (five types in this example) of protein expression base sequencesand an oligonucleotide having a protein collection material thatcollects the expressed proteins are fixed beforehand to the fixingregion 58 of the biological material fixed region enclosing tip 51 shownin FIG. 6 with a spacing. In order to fix these materials, a functionalgroup is generated or expressed on the fixing region 58. Consequently,the generated amount of the generated protein, and the bondability witha specific protein are examined. In the present example, the fixingregion 58 is formed on one plane face of the plate-shaped carrier 57formed separate to the tip form vessel 52, and the oligonucleotide isfixed to the predetermined fixing positions. Subsequently, the surfaceformed with the fixing region 58 of the plate-shaped carrier 57 is facedto the fluid contact opening section 59 side so as to form an inner wallface of the tip form vessel 52 interior, and is fitted to the tip formvessel 52 so as to cover the fluid contact opening section 59, tothereby enclose the fixing region 58, and form the biological materialfixed region enclosing tip 51.

On the other hand, within the respective single liquid storage sections100 a of the eight consecutive cartridge vessels 100 provided to the tipprocessing region 81 of FIG. 7, solutions of amino acids, ribosomes, orthe like, are stored, a cleaning solution (hereunder referred to as“PBS-T”) comprising a PBS buffer solution and a 0.05% Tween 20 buffersolution, which is a surface active agent is stored in the liquidstorage sections 100 b to 100 g, a 5% skim milk suspension in PBS-T isstored in the liquid storage sections 100 h, and a solution of anantibody labeled with a fluorescent material, and a biotinylatedmaterial is stored in the liquid storage sections 100 i.

In a step S21, in regard to a biological material fixed region enclosingtip 51 that is formed in this manner, the nozzle 117 of the biologicalmaterial fixed region enclosing tip processing device 80 is installed tothe installation opening part 54 provided on the upper side thereof.Next, as shown in FIG. 11( a) and (b), the eight consecutive nozzles 117of the collective nozzle head 84 of the biological material fixed regionenclosing tip processing device 80 are simultaneously moved to theliquid storage section 100 a of the cartridge vessels 100, and an amountv6 (for example, approximately 500 microliters) of the solution of theamino acid, or the like, that is stored in the liquid storage sections100 a is suctioned into the tip form vessel 52 at a speed s6 (forexample, approximately 760 to 1700 microliters/sec). In this state, theinside of the tip form vessel 52 is heated by flowing an electricalcurrent to the conductive thin film 57 a that is formed so as to coverthe outside surface of the tip form vessel 57, and it is maintained at37° C. for 1 hour.

In a step S22, following discharge of the liquid from the narrow tube51, as shown in FIG. 11( c), the collective nozzle head 84 is moved tothe liquid storage sections 100 b, and it is washed by repeating suctionand discharge of the PBS-T solution with respect to the fixing regionforming section 53, for example, ten times, at a speed s7 (for example,from approximately 760 to 1700 microliters/sec), and in an amount v7(for example, approximately 500 microliters). This operation is alsorepeated at the liquid storage sections 100 c.

In a step S23, as shown in FIG. 11( d), the collective nozzle head 84 ismoved to the liquid storage sections 100 h, the PBS-T and 5% skim milksuspension is suctioned, then reacted in a room temperature state forapproximately 1 hour, and blocking is performed.

In a step S24, following discharge of the liquid from the narrow tube55, the collective nozzle head 84 is moved to the liquid storagesections 100 d, and it is washed by repeating suction and discharge ofthe PBS-T solution with respect to the narrow tube 55, for example, tentimes, at a speed s8 (for example, from approximately 760 to 1700microliters/sec), and in an amount v8 (for example, approximately 500microliters). This operation is also repeated at the liquid storagesections 100 e.

In a step S25, as shown in FIG. 11( f), the biological material fixedregion enclosing tip 51 is transported to the liquid storage sections100 i, and the suspension which suspends an antibody that has beenlabeled by the fluorescent material, and a biotinylated material, issuctioned, and incubated at room temperature for approximately 30minutes to 1 hour.

Furthermore, in a step S26, as shown in FIG. 11( g), it is transportedto the liquid storage sections 100 f, and it is washed by repeatingsuction and discharge of the PBS-T solution with respect to the narrowtube 55, for example, ten times, at a speed s9 (for example,approximately 760 to 1700 microliters/sec), and in an amount v9 (forexample, approximately 500 microliters). This operation is also repeatedat the liquid storage sections 100 g.

In a step S27, in regard to the biological material fixed regionenclosing tip 51, the collective nozzle head 84 is moved to the tipstorage section 102 that is stopped on the column transporting route 103a of the conveyor 103, separated from the plurality of consecutivenozzles 117 provided to the collective nozzle head 84 by means of theclaw 122 and stored in the tip storing section 102 that is arranged onthe column transporting route 103 a, and transported along thetransporting route by driving the conveyor 103. At the time the tipstorage section 102 reaches the row transporting route 103 b, theindividual nozzle head 84′ is moved to the reagent storage section 77, apredetermined reagent is suctioned, and then, amongst the eight tipstorage sections 102 that are stopped along the row transporting route103 b, it is moved to the selected biological material fixed regionenclosing tip 58, and dispensing of the predetermined reagent isperformed from the installation opening part 54 of the biologicalmaterial fixed region enclosing tip 58. Thereafter, at the measurementposition 104 provided on the transporting route, light from the fixingregion 58 is received and measured at the light receiving section 106,the fluorescence strength of the particle surface is measured, and theprotein that has reacted with the antibody labeled with the fluorescentmaterial, the biotinylated material, or the like, is specified, or theexpression amount thereof is measured from the strength and the lightemission position thereof.

Furthermore it is possible to use a biological material fixed regionenclosing tip processing device 180 according to another embodimentshown in FIG. 12 instead of the biological material fixed regionenclosing tip processing device 80 shown in FIG. 7 and FIG. 8. In FIG.12, the same reference symbols as in FIG. 7 and FIG. 8 indicate the samecomponents. The biological material fixed region enclosing tipprocessing device 180 is one in which suction and discharge of gas isperformed using a nozzle that is communicated with a suction anddischarge mechanism, although the biological material fixed regionenclosing tip processing device 180 has a nozzle head 184 that has aplurality of consecutive (nine consecutive in this example) nozzles 117that are arranged in the column direction (the vertical direction in thedrawing), and with respect to the nozzle head 184, it differs to thenozzle head 84 in that suction and discharge is simultaneously performedby the same suction and discharge mechanism. Amongst the nineconsecutive nozzles 117, one nozzle 117 of the end is an individualnozzle, and as shown by the position thereof (the position of referencesymbol 112 b in FIG. 12), it is provided such that it is somewhatseparated from the eight consecutive nozzles 117, that is to say, theposition of the collective nozzle (the position of reference symbol 112a in FIG. 12).

In regard to the suction and discharge mechanism, it has a wide diametersection 116 provided to a somewhat upper section of the nozzles 117, anda rod 112 for sliding a plunger 115 a within a cylinder 115 that isjoined to the nozzles 117. Furthermore, the nine rods 112 are installedsuch that they sit on eight consecutive end sections 112 a and a singleend section 112 b, that have a larger diameter than the rods 112 andprotrude in the radial direction from the eight respective notchsections that are provided to the edge of a driving plate 123, in whichsimultaneous vertical movement is possible. Hence, the nozzle head 184simultaneously moves in the row direction (the horizontal direction orthe left and right directions on the drawing).

Amongst the nine consecutive nozzles 117, the individual nozzle isprovided to the nozzle head 184. Hence the suction and discharge issimultaneously performed together with the other eight consecutivecollective nozzles. Furthermore, also in regard to the raising andlowering mechanism, it is simultaneously performed with respect tohorizontal movement in the row direction (the left and right directionsin FIG. 12). However, the individual nozzle is, in the reagentdispensing region 82, used for dispensing reagents for measurement intothe biological material fixed region enclosing tip 11. In a case wherethe individual nozzle is used, it is in a state where the biologicalmaterial fixed region enclosing tip has been removed from the othercollective nozzles. Furthermore, in a case where the collective nozzlesare used, it is in a state where the tip form vessel, or the like, isnot installed to the individual nozzle.

The embodiments above have been specifically explained in order tobetter understand the present invention, and do not restrict otherembodiments in any way. Accordingly, they are changeable within a scopethat does not depart from the gist of the invention. For example, in theembodiments, although only the cases of DNA and proteins were explained,it may also be a sugar chain, other DNA materials, RNA, or the like.Furthermore, as the fixing region, although only the case where this isprovided on one plane face was explained, the fixing region may also beone which is provided on a curved surface, or on two plane faces or onthe faces of a solid body. Furthermore, in regard to the numericalvalues, the frequencies, the shapes, the numbers, the quantities, or thelike, that were used in the explanations above, they are not restrictedto these cases in any way.

Moreover, in the present invention, as the fixing region, it is alsopossible to use one where a narrow and long member, such as a threadform, with a flexibility, or a thread form, in which one or more typesof biological materials, such as a ligand, are provided such that theyare fixed or are fixable, is wound around a carrier. In short, it can beused as the carrier as long as it is one where suction and discharge offluid can be performed in a state where it is maintained within thefixing region forming section.

Furthermore, by suppressing the chemical material containing the ligand,or the like, with respect to all side faces of the narrow and longmember to a low concentration, production is simplified and thereliability thereof is increased, and on the other hand, at the time ofprocessing, by storing the integrated narrow and long member, theprocessing efficiency can be increased. Furthermore, since at the timeof measurement the arrangement of chemical materials can be handled withcertainty along a one-dimensional route, the reliability of measurementis high. An example of a narrow and long member with flexibilityincludes, for example, those that are formed by chemical fibers, such asnylon.

Moreover, the configuration elements above, such as the fixing region,the carriers, the narrow tubes, the nozzle head, the tip form vessel,the sealing section, and the nozzle, as well as the fixing regionforming section, the temperature raising and lowering device or thelike, and the devices, can be arbitrarily combined while making suitablechanges. Furthermore, the ligand is not restricted to DNA, and itincludes genetic material such as oligonucleotides and RNA, immunitymaterials, sugar chains, and further includes pheromones, allomones,mitochondria, viruses, and plasmids.

Furthermore, the aforementioned reagents and materials show examples,and it is also possible to utilize other reagents and materials.Moreover, a carrier in which DNA, or the like, has been collected can betaken out from the narrow tube, or the like, and it can be made thesubject of preservation, or other processes.

INDUSTRIAL APPLICABILITY

The present invention relates to a biological material fixed regionenclosing tip, a biological material fixed region treatment apparatusand a method thereof. The present invention relates to all fields, suchas fields in which handling of biopolymers, such as genes, the immunesystem, amino acids, proteins, and sugars, and biological low molecularweight compounds is demanded, for example, in agricultural fields suchas engineering fields, food products, agricultural produce and seafoodprocessing, medical fields such as pharmacology fields, sanitation,immunity, diseases, and genetics, and science fields such as chemistryor biology. The present invention is, in particular, an effective methodin cases where a series of processes using a plurality of reagents andmaterials is continuously executed in a predetermined order.

BRIEF DESCRIPTION OF THE REFERENCE SYMBOLS

-   -   10 Biological material fixed region treatment apparatus    -   11, 22, 32, 41, 51 Biological material fixed region enclosing        tip    -   12, 23, 33, 42, 52 Tip form vessel    -   13, 24, 34, 43, 53 Fixing region forming section    -   17, 48, 58 Fixing region    -   18, 49, 57 Plate-shaped carrier    -   18 a Annular attachment section (enclosing section)    -   30, 40, 50 Lid member (enclosing section)    -   84 Collective nozzle head    -   84′ Individual nozzle head    -   103 Conveyor (queued route transporting device)    -   106 Light receiving section    -   184 Nozzle head

1. A biological material fixed region enclosing tip comprising: a tipform vessel having an installation opening part that is installable to anozzle that performs suction and discharge of gas, and an opening,through which inflow and outflow of fluid is possible by means of saidsuction and discharge of gas; a fixing region provided inside said tipform vessel, in which a predetermined biological material is fixed orfixable in a plurality of different positions that are determinedbeforehand that are distinguishable from the exterior, which enablesanalysis of target biological material by measuring light emitted atsaid positions; and an enclosing section that encloses the fixing regionwithin the tip form vessel such that the fixing region is able to makecontact in an immovable state with the fluid that has flown into the tipform vessel from the opening, and said tip form vessel is provided witha narrow tube that is provided with said opening in the end, and isformed narrower than said installation opening part, and so that it isinsertable into various vessels, and a wide tube which has translucence,with said fixing region formed between said narrow tube and saidinstallation opening part.
 2. A biological material fixed regionenclosing tip according to claim 1, wherein said fixing region isprovided on said plane form carrier which is detachably attached insidesaid tip form member, and said tip form member has a carrier insertionopening insertable by said plane form carrier, and said enclosingsection is attached inside said tip form member, so that fluid that hasflown in from said opening inside said tip form member is able tocontact with said plane form carrier.
 3. A biological material fixedregion enclosing tip according to claim 1, wherein said tip form vesselhas a distribution opening that is capable of distributing saidbiological material with respect to said fixing region, and saidenclosing section has a lid member that covers the distribution opening,so that fluid that has flown in from said opening can contact with saidfixing region.
 4. A biological material fixed region enclosing tipaccording to claim 3, wherein said fixing region is provided on aninternal surface of said tip form vessel, and said distribution openingis provided on a wall facing said internal surface.
 5. A biologicalmaterial fixed region enclosing tip according to claim 1, wherein thevolume of a space in which liquid is storable within the tip form vesselwith said fixing region enclosed is several microliters to severalhundred microliters.
 6. A biological material fixed region enclosing tipaccording to claim 1, wherein said fixing region is formed on one faceof the plane form carrier, and on said tip form vessel there is provideda fluid contact opening part for enabling contact between said fixingregion of said plane form carrier and fluid that has been introducedfrom said opening, and said enclosing section has an attaching memberthat attaches said plane form carrier from outside of said tip formvessel so that said fixing region of said plane form carrier ispositioned in said contact opening part.
 7. A biological material fixedregion enclosing tip according to claim 1, wherein the entire wall ofsaid tip form vessel, or a portion thereof, is formed by anelectroconductive member that has a predetermined electrical resistancevalue.
 8. A biological material fixed region treatment apparatuscomprising: a nozzle head that has one or a plurality of consecutivenozzles that perform suction and discharge of gas; a suction anddischarge mechanism that performs suction and discharge of gas via thenozzles; one or two or more biological material fixed region enclosingtips that have an installation opening part that is installed or isinstallable to said nozzles and an opening through which inflow andoutflow of fluid is possible by means of the suction and discharge ofthe gas, and that have a tip form vessel that is provided with a narrowtube that is provided with said opening in the end, and is formednarrower than said installation opening part, and so that it isinsertable into various vessels, and a wide tube which has translucence,with said fixing region formed between said narrow tube and saidinstallation opening part, and in which a fixing region in whichpredetermined biological material is fixed in a plurality of differentpositions that are determined beforehand that are distinguishable fromthe exterior, which enables analysis of target biological material bymeasuring light emitted at said positions provided inside said tip formvessel, is enclosed; a stage to which a liquid storage section group, inwhich a variety of liquids are stored or are storable, is provided; amovement device that relatively moves said nozzle head with respect tosaid liquid storage section group; and a control section that controlsthe suction and discharge operations comprising the amount, the speed,the frequency, the time, or the position of the suction and discharge ofsaid nozzles based on; the structure of said biological material fixedregion enclosing tip, the material conditions comprising the type ofbiological material that is fixed to the fixing region or is presentwithin the fluid, the concentration, the amount of liquid, and thecoordinate position containing the storage position of the liquid, andthe processing contents.
 9. A biological material fixed region treatmentapparatus according to claim 8, further comprising a light receptiondevice that receives light from said fixing region stored within saidtip form vessel.
 10. A biological material fixed region treatmentapparatus according to claim 8, wherein a space in which liquid isstorable within said tip form vessel, is several microliters to severalhundred microliters.
 11. A biological material fixed region treatmentapparatus according to claim 8, wherein a temperature raising andlowering body that raises and lowers the temperature as a result of asignal from the exterior is provided in the vicinity of, making contactwith, or able to be in the vicinity of or making contact with, theoutside of said tip form vessel of said biological material fixed regionenclosing tip.
 12. A biological material fixed region treatmentapparatus according to claim 8, wherein said nozzle head has acollective nozzle head in which a plurality of consecutive nozzles arearranged along the column direction and an individual nozzle head thathas at least one nozzle, said suction and discharge mechanism has acollective suction and discharge mechanism that simultaneously performssuction and discharge of gas with respect to the plurality ofconsecutive nozzles of said collective nozzle head, and an individualsuction and discharge mechanism that individually performs suction anddischarge of gas with respect to each nozzle of said individual nozzlehead, and said movement device has, a nozzle head movement device thatrelatively moves said collective nozzle head and said individual nozzlehead in said row direction with respect to said liquid storage sectiongroup, and a transporting route that includes a column transportingroute that is on the movement route of said collective nozzle head andalong said column direction and a row transporting route that is on themovement route of said individual nozzle head and along said rowdirection, and has a queued route transporting device that transports atransport storage section, in which tips that have been detached fromsaid collective nozzle head or liquid that has been discharged from saidcollective nozzle head are respectively storable, along saidtransporting route.
 13. A biological material fixed region treatmentapparatus according to claim 8, wherein said nozzle head has a pluralityof consecutive collective nozzles and one individual nozzle arrangedalong the column direction, said suction and discharge mechanismsimultaneously performs suction and discharge of gas with respect to thecollective nozzles and the individual nozzle of said nozzle head, andsaid movement device has, a nozzle head movement device that relativelymoves said nozzle head along the row direction with respect to a stagethat has said liquid storage section group, and a transporting routethat includes a column transporting route that is on the movement routeof said collective nozzles and along said column direction and a rowtransporting route that is on the movement route of said individualnozzle and along said row direction, and has a queued route transportingdevice that transports a transport storage section, in which tip formvessels that have been detached from said collective nozzle or liquidthat has been discharged from said collective nozzle head arerespectively storable, along said transporting route.
 14. A biologicalmaterial fixed region treatment apparatus according to claim 12, whereina light reception device, which receives light from said transportstorage section, is provided at a predetermined position along saidtransporting route of said queued route transporting device.
 15. Abiological material fixed region treatment method comprising: a fixingstep for fixing a predetermined biological material to a fixing regionsuch that it is associated with a predetermined position by apredetermined relationship; an enclosing step for forming a biologicalmaterial fixed region enclosing tip by enclosing within a tip formvessel which has an installation opening part that is installable to oneor a plurality of consecutive nozzles that perform suction and dischargeof gas, and an opening, through which inflow and outflow of fluid ispossible by means of the suction and discharge of gas, and that isprovided with a narrow tube that is provided with said opening in theend, and is formed narrower than said installation opening part, and sothat it is insertable into various vessels, and a wide tube which hastranslucence, with said fixing region formed between said narrow tubeand said installation opening part, said fixing region fixed with saidbiological material, which enables analysis of target biologicalmaterial by measuring light emitted at said positions, such that saidfixing region is able to make contact in an immovable state with thefluid that has flown into said tip form vessel from said opening; and areaction step for moving a nozzle to which one or two or more of saidbiological material fixed region enclosing tips has been installed to apredetermined liquid storage section, and bringing into contact andreacting the biological material fixed to said fixing region and asolution stored in the liquid storage section by controlling theoperation of suction and discharge, which comprises the amount ofsuction and discharge via said nozzle, the speed, the frequency, thetime, and the location, based on the structure of said biologicalmaterial fixed region enclosing tip, the material conditions comprisingthe type of biological material that is fixed to said fixing region oris present in the solution, the concentration, the amount of solution,or the position coordinate which includes the storage position of thesolution, and the processing contents.
 16. A biological material fixedregion treatment method according to claim 15, that, following saidreaction step, has a light reception step for receiving light from saidfixing region of said biological material fixed region enclosing tip.17. A biological material fixed region treatment method according toclaim 15, wherein said reaction step has a temperature raising andlowering step for raising and lowering the temperature within saidbiological material fixed region enclosing tip.
 18. A biologicalmaterial fixed region treatment method according claim 15, wherein saidfixing step is performed by distributing in a fixing region provided onan internal surface of said tip form vessel, said biological materialthat has passed through a distribution opening provided in said tip formvessel, and said enclosing step is performed by covering saiddistribution opening with a lid member, which is attached from outsideof said tip form vessel.